Oxidative Stress and ROS Link Diabetes and Cancer

Round 1

Reviewer 1 Report

Dear Author,

 I have revisited your manuscript, which you first submitted to the journal "Cancers." I'm pleased to note that some of the minor changes I previously recommended have been incorporated, so here I will be straightforward. While I still encourage you to make an additional effort to condense your overall text, I am inclined to believe that, considering the feedback from other reviewers, your manuscript could be deemed suitable for publication.

Furthermore, I strongly recommend enhancing the quality of your images and, whenever possible, retaining only those that substantially contribute to your review.

Best regards.

While not obligatory, and without compromising the publication's quality, it would greatly benefit the manuscript to undergo proofreading by an individual proficient in scientific English grammar.

Author Response

This reviewer is an original reviewer when the manuscript was invited and submitted to CANCERS. The reviewer states that “I’m pleased that some of the minor changes I previously recommended have been incorporated”. The reviewer encourages me to make an additional effort to condense the overall text, “I am inclined to believe that, considering the feedback from other reviewers, your manuscript could be deemed suitable for publication.

The reviewer recommends enhancing the quality of the images and retaining only those that substantially contribute to the review.

The reviewer further states, “While not obligatory, and without compromising the publication’s quality, it would greatly benefit the manuscript to undergo proofreading by an individual proficient in scientific English grammar.

I am pleased that the reviewer recognizes the merit of this review and that it is deemed suitable for publication. With regard to suggestions of condensation of the review, the following individual issues have been addressed:

Response:

Condense the text: This is the third time this reviewer has reviewed the manuscript. The original version for “CANCERS” was 9, 154 words, excluding Bibliography. The first revision for “CANCERS” was 9,078 words and 37 pages. This version was revised for “JMP” with a word count of 8,588 and with the suggested elimination of some Figures (as recommended), the page number was reduced to 24. The manuscript was written with, not only a review of the literature of the link of Oxidative Stress produced by Reactive oxygen species (ROS) in Diabetes that increased the risks of certain cancers, but also to pedagogically provide an understanding of how these ROS are produced - for those readers with a more clinical bent that might require this understanding. Further reduction in length of the manuscript would necessarily result in loss of this thread of continuity.

Quality of Images: I agree that the quality of Figures 4 and 5 might be improved and I have made improvements to these figures.

Proofreading by individual proficient in scientific English grammar: This is an interesting criticism as the second reviewer detected no issues in this metric and provided a five-star rating. However, I have carefully reviewed the manuscript for awkward sentence structure, etc. and made revisions where appropriate. It would have been beneficial if this reviewer had indicated where in the manuscript the grammatical deficiencies occurred. I hope that this reviewer found no systemic problems as I had taught scientific writing for several semesters at university level.

Reviewer 2 Report

A review, Oxidative Stress and ROS Linking Diabetes and Cancer by Homer S. Blackis is an oversimplification of two highly complex pathologic phenotypes like diabetes and cancer.  Chronic inflammation and ROS in diabetes and cancer have been covered in numerous reviews.  It is not apparent to me how information in this review adds to the preexisting knowledges.

As stated by the author, diabetes is associated with an increased risk of many types of cancer including pancreas, colon, liver, bladder, breast, endometrial, and non-Hodgkin’s lymphoma.  It is unlikely that ROS-altered pathways by diabetic conditions would explain the development of these cancer. 

It is increasing apparent that conventional approaches and concepts are not sufficient to explain cancer phenotype. It would thus be useful to audiences if the author provides current views on oncogenic mechanisms. Then, look for evidence for these key elements in diabetes. Please see a review by Drochioiu, G. 

Drochioiu, G. Multifactorial Distress, the Warburg Effect, and Respiratory and pH Imbalance in Cancer Development. Stresses 2023, 3, 500-528. https://doi.org/10.3390/stresses3020036

Suggestions

o   It would be useful if a review is focused on a specific type of cancer.

o   It would be useful to audiences, if results of numerous on-going clinical trials with various anti-oxidants are provided (in a summary table format).

Comments for author File: Comments.pdf

Author Response

1. States that the review is an oversimplification of two highly complex pathologic phenotypes like diabetes and cancer. The reviewer fails to understand how the information in the review adds to the preexisting knowledge.
2. Reviewer states that it is unlikely that ROS-altered pathways by diabetic conditions would explain the development of cancer.
3. Reviewer suggests an entirely different approach to explain cancer phenotype and then look for evidence for these key elements in diabetes. Suggests addition of review by Drochiolu, G.
4. Reviewer suggests review could be focused on a specific type of cancer.
5. Suggests that tr would be useful if results of on-going clinical trials with various antioxidants be provided in a summary table format.

Response:

(1-2) The reviewer failed to recognize the intent of this review that is clearly stated on page 2, line 67. “It is the intent of this review to examine the link of these ROS-altered pathways in T2DM to cancer expression”.  The reviewer also states that the review is an oversimplification of two highly complex pathologic phenotypes like diabetes and cancer.  Indeed, lines 254-260 have been revised to recognize the complexities of the diabetes and cancer phenotypes. An explanation for the synthesis of T2DM in a general comprehensive overview is provided as it is imperative that the role of oxidative stress and ROS formation is diabetes be described as the confluence of these diabetic responses provide the background linking diabetes to increased cancer risk.

(3) The reviewer suggests an entirely different approach to explain the cancer phenotype and then look for evidence for these elements in diabetes. The reviewer fails to recognize that it is increased cancer risk linked to diabetes that is the topic of this review. I would be quite famous if I could explain the cancer phenotype. Reviewer suggests citing a review by Grochioiu. I am grateful for this recommendation as it provides additional evidence that supports the role of ROS as a stressor and a signaling molecule for disease development. This review was not published at the time  my literature search ended. . However, I have added it and made the appropriate citation changes necessitated.

(4) If the review focused upon a particular type of cancer, it would not address the link to increased risk for a range of cancers.

(5) If the reviewer wants to examine results of a number of on-going clinical trials with various antioxidants, then I would direct the reviewer to reference 45 and other references cited in the 2.3 Antioxidant defense in maintaining redox balance section. To place synthesized data in a tabular format on this topic is not a major objective of this review. The review does, however, accurately reports results of a number of these antioxidant studies.

Round 2

Reviewer 2 Report

Thank you for the clarification given and for revising part of the manuscript.  I still believe that it would strengthen the author’s argument if a positive outcome of any clinical trial with any antioxidants can be documented. These perhaps can be extracted from the reference 45. The risk of different types of cancers associated with diabetes are not the same.

Author Response

I have addressed the reviewer’s concerns and made a revision, highlighted, line 215-221. There is no reason to list positive clinical trials that report only associations. The Intervention trials, the gold standard, have been disappointing and have led to the closing of clinical trials, e.g. (Caret) because of adverse effects. The reviewer can get a better insight into these trials in Reference 45. Listing clinical trials was not the intent or part of the rationale for this review and the reviewer can go to the pertinent literature.

Reviewer: Suggests that the manuscript would be strengthened if positive outcomes of any clinical trials with antioxidants could be documented.

Response: There have been a number of clinical trials, observational studies of case-control design, in which associations of lower antioxidant levels are associated with higher cancer risk. These include trials for skin, breast, prostrate, colon, and lung cancers – all discussed in detail in Reference 45. The listing of positive clinical trials is rather meaningless as intervention trials (the gold standard) have been disappointing, - reporting no or adverse effects of antioxidant supplementation. These have led both the IARC and World Cancer Fund/AICR to withdraw recommendation for antioxidant supplementation for general cancer prevention. That is why I have recommended, in the manuscript, that antioxidant therapy to reduce the risk of cancer in diabetic patients should be initiated in the pre-diabetic stage (early stage of hyperglycemia) of disease and break the link, as later treatment may, because of the bimodal nature of the cancer/antioxidant response, may lead to an increase in metastasis.

I hope that this will satisfy the requirement for acceptance.

Sincerely.

Homer S. Black